Stroke the third largest cause of death and is a leading cause of serious, long-term disability in the United States and worldwide. Of the 700,000 Americans who will survive a stroke this year, 70% receive some form of motor rehabilitation. However, the efficacy of current motor rehabilitation interventions is highly variable and reflects our lack of understanding of the neural and behavioral signals driving functional recovery. Motor recovery is supported by functional compensation within residual motor areas including primary motor cortex. The neural mechanisms underlying functional reorganization within motor cortex involve synaptic plasticity within cortical circuitry that is driven by specific neural signaling pathways. We hypothesize that some of the variability in the efficacy of motor rehabilitation interventions is due to inherent differences in the capacity for experience-dependent plasticity. Specifically, polymorphisms within genes that govern the activity of neural signaling pathways mediating synaptic plasticity can influence the rate and level of motor recovery after stroke. The goals of the proposed set of experiments are to characterize the relationship between genotype, cortical plasticity and motor performance. The studies will use blood genotyping, transcranial magnetic stimulation and extensive motor training/testing to examine determine how naturally occurring polymorphisms in the Brain Derived Neurotrophic Factor (BDNF) gene, known to be involved in mediating cortical plasticity, influence the capacity for cortical plasticity, age related decrements in motor performance and capacity for motor recovery after stroke. The experiments will be conducted in both young and old subjects with or without the polymorphism. We hypothesize that age related decrements in motor status and motor impairments after stroke will be exacerbated in polymorphic individuals and that this represents a compromised capacity for compensation that occurs in response to age and stroke related declines in neural function. This process is particularly important for stroke victims receiving rehabilitation to improve motor function. The short term goal of these experiments is to establish the baseline role of these different genotypes in experience-dependent plasticity in the intact brain. The long term goal of this research program is to determine how genotype may influence the capacity for motor recovery after stroke Using transcranial magnetic stimulation we will examine changes in corticospinal output in response to motor training in young, middle aged and old subjects with three variants of the BDNF genotype. We will further examine the relationship between experience- dependent cortical plasticity, motor function and age. Finally we will examine how the capacity for rehabilitation-dependent motor recovery in stroke patients varies as a function of BDNF genotype.